rs1065852

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000106.6(CYP2D6):c.100C>T(p.Pro34Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,605,342 control chromosomes in the GnomAD database, including 48,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,drug response,other (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.19 ( 4032 hom., cov: 31)

Exomes 𝑓: 0.21 ( 44366 hom. )

Consequence

CYP2D6
NM_000106.6 missense

Scores

Clinical Significance

Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:1O:5

Conservation

PhyloP100: 7.37

Variant links:

Genes affected

CYP2D6 (HGNC:2625): (cytochrome P450 family 2 subfamily D member 6) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize as many as 25% of commonly prescribed drugs. Its substrates include antidepressants, antipsychotics, analgesics and antitussives, beta adrenergic blocking agents, antiarrythmics and antiemetics. The gene is highly polymorphic in the human population; certain alleles result in the poor metabolizer phenotype, characterized by a decreased ability to metabolize the enzyme's substrates. Some individuals with the poor metabolizer phenotype have no functional protein since they carry 2 null alleles whereas in other individuals the gene is absent. This gene can vary in copy number and individuals with the ultrarapid metabolizer phenotype can have 3 or more active copies of the gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

CYP2D6 links:

NDUFA6-DT (HGNC:45273): (NDUFA6 divergent transcript)

NDUFA6-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002202928).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6 linkuse as main transcript	c.100C>T	p.Pro34Ser	missense_variant	1/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3 linkuse as main transcript	c.100C>T	p.Pro34Ser	missense_variant	1/8		NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2 linkuse as main transcript	c.100C>T	p.Pro34Ser	missense_variant	1/9		NM_000106.6	ENSP00000496150	P1	P10635-1
NDUFA6-DT	ENST00000439129.5 linkuse as main transcript	n.1718+5285G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

28692

AN:

150496

Hom.:

4035

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.301

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.541

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.223

Gnomad OTH

AF:

0.177

GnomAD3 exomes

AF:

0.209

AC:

50363

AN:

241260

Hom.:

7878

AF XY:

0.207

AC XY:

27069

AN XY:

130794

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.242

Gnomad EAS exome

AF:

0.577

Gnomad SAS exome

AF:

0.157

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.217

Gnomad OTH exome

AF:

0.199

GnomAD4 exome

AF:

0.214

AC:

311907

AN:

1454734

Hom.:

44366

Cov.:

AF XY:

0.213

AC XY:

153913

AN XY:

723174

show subpopulations

Gnomad4 AFR exome

AF:

0.121

Gnomad4 AMR exome

AF:

0.126

Gnomad4 ASJ exome

AF:

0.245

Gnomad4 EAS exome

AF:

0.481

Gnomad4 SAS exome

AF:

0.157

Gnomad4 FIN exome

AF:

0.119

Gnomad4 NFE exome

AF:

0.220

Gnomad4 OTH exome

AF:

0.211

GnomAD4 genome

AF:

0.190

AC:

28678

AN:

150608

Hom.:

4032

Cov.:

AF XY:

0.186

AC XY:

13671

AN XY:

73610

show subpopulations

Gnomad4 AFR

AF:

0.124

Gnomad4 AMR

AF:

0.153

Gnomad4 ASJ

AF:

0.246

Gnomad4 EAS

AF:

0.541

Gnomad4 SAS

AF:

0.167

Gnomad4 FIN

AF:

0.113

Gnomad4 NFE

AF:

0.223

Gnomad4 OTH

AF:

0.175

Alfa

AF:

0.212

Hom.:

1373

Bravo

AF:

0.192

ESP6500AA

AF:

0.120

AC:

525

ESP6500EA

AF:

0.224

AC:

1924

ExAC

AF:

0.204

AC:

24731

Asia WGS

AF:

0.287

AC:

996

AN:

3464

ClinVar

Significance: Likely benign; drug response; other

Submissions summary: Benign:1Other:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Tamoxifen response

Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

May 01, 2019

CYP2D6*10 has decreased function: individuals with one decreased function and one no function allele (e.g., *4/*10) are intermediate metabolizers; individuals with two decreased function alleles (e.g. *10/*10) are normal metabolizers or intermediate metabolizers (controversy remains). Therapeutic recommendations from professional societies state that intermediate metabolizers may benefit less from tamoxifen therapy because they have lower concentrations of tamoxifen's major active metabolite, endoxifin, compared with normal metabolizers. For tamoxifen, CPIC prescribing recommendations for individuals with an activity score (AS) of 1.0 are allele dependent, based on the presence of the *10 allele: if a *10 allele is present, individuals are provided a 'moderate' recommendation; if *10 is NOT present, individuals are graded as 'optional' because the recommendations are primarily extrapolated from evidence generated from *10 individuals (i.e., limited data for clinical outcomes and pharmacokinetics for this group). Individuals with one decreased function and one no function allele (e.g. *4/*10) are intermediate metabolizers. Individuals with two decreased function alleles (e.g. *10/*10) are normal metabolizers or intermediate metabolizers (controversy remains).

Tramadol response

Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Debrisoquine, poor metabolism of

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Aug 08, 2023

- -

Deutetrabenazine response

Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

May 01, 2019

not provided

Other:1

other, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 06, 2018

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

T;T;T;T;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

.;.;T;T;T

MetaRNN

Benign

0.0022

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

4.1

H;H;H;.;H

MutationTaster

Benign

5.2e-8

P;P;P

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-7.4

.;.;D;.;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.023

.;.;D;.;D

Sift4G

Uncertain

0.025

.;.;D;D;D

Vest4

0.21, 0.42, 0.49

MPC

0.48

ClinPred

0.078

GERP RS

3.5

Varity_R

0.55

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over